tbuckley/cabot-search huggingface dataset:
Development and validation of a prognostic model incorporating tumor thrombus grading for nonmetastatic clear cell renal cell carcinoma with tumor thrombus: A multicohort study
Authors: Le Qu, Hui Chen, Qi Chen, Silun Ge, Aimin Jiang, Nengwang Yu, Yulin Zhou, Michał Kunc, Ye Zhou, Xiang Feng, Wei Zhai, Zhenjie Wu, Miaoxia He, Yaoming Li, Rui Chen, Bo Han, Xing Zeng, Yao Fu, Changwei Ji, Xiang Fan, Guangyuan Zhang, Cheng Zhao, Taile Jing, Chenchen Feng, Hongwei Zhao, Di Sun, Liang Wang, Sheng Tai, Cheng Zhang, Shaohao Chen, Yixun Liu, Haifeng Wang, Jinli Gao, Yufeng Gu, He Miao, Tangliang Zhao, Xiaoming Yi, Chaopeng Tang, Dian Fu, Haowei He, Qiu Rao, Wenquan Zhou, Ning Xu, Gongxian Wang, Chaozhao Liang, Zhiyu Liu, Dan Xia, Xiongbing Zu, Ming Chen, Hongqian Guo, Weijun Qin, Zhe Wang, Wei Xue, Benkang Shi, Shaogang Wang, Junhua Zheng, Cheng Chen, Łukasz Zapała, Jingping Ge, Linhui Wang
Journal: MedComm (2023)

There is significant variability with respect to the prognosis of nonmetastatic clear cell renal cell carcinoma (ccRCC) patients with venous tumor thrombus (VTT). By applying multiregion whole-exome sequencing on normal-tumor-thrombus-metastasis quadruples from 33 ccRCC patients, we showed that metastases were mainly seeded by VTT (81.8%) rather than primary tumors (PTs). A total of 706 nonmetastatic ccRCC patients with VTT from three independent cohorts were included in this study. C-index analysis revealed that pathological grading of VTT outperformed other indicators in risk assessment (OS: 0.663 versus 0.501-0.610, 0.667 versus 0.544-0.651, and 0.719 versus 0.511-0.700 for Training, China-Validation, and Poland-Validation cohorts, respectively). We constructed a risk predicting model, TT-GPS score, based on four independent variables: VTT height, VTT grading, perinephric fat invasion, and sarcomatoid differentiation in PT. The TT-GPS score displayed better discriminatory ability (OS, c-index: 0.706-0.840, AUC: 0.788-0.874; DFS, c-index: 0.691-0.717, AUC: 0.771-0.789) than previously reported models in risk assessment. In conclusion, we identified for the first-time pathological grading of VTT as an unheeded prognostic factor. By incorporating VTT grading, the TT-GPS score is a promising prognostic tool in predicting the survival of nonmetastatic ccRCC patients with VTT.
Persistence of second-line biologics in psoriasis after first-line biologic failure: a nationwide cohort study from the French health insurance database (SNDS)
Authors: Clarisse Marcombes, Laetitia Penso, Alain Weill, Rosemary Dray-Spira, Mahmoud Zureik, Emilie Sbidian
Journal: British Journal of Dermatology (2023)

Many biologics are available for psoriasis and have been compared in real-life studies based on their persistence (i.e. time between initiation and discontinuation). However, after first-line biologic failure, data are lacking on the choice of second-line biologic among the four available classes [tumour necrosis factor inhibitors (TNFi); interleukin (IL)-12/IL-23 inhibitor (IL-12/IL-23i); IL-17 inhibitors (IL-17i); and IL-23 inhibitors (IL-23i)].To compare the long-term persistence of available second-line biologics in psoriasis according to prior exposure.This nationwide cohort study involved the administrative healthcare database of the French health insurance scheme linked to a hospital discharge database. Participants were adults with psoriasis, defined as having at least two prescriptions of a topical vitamin D derivative within a 2-year period, with initiation of a second-line biologic between 1 January 2015 and 31 December 2021. We included patients who initiated a second-line biologic directly after first-line discontinuation (i.e. without a 'washout' period). The end of follow-up was 30 June 2022. Discontinuation was defined as > 90 days without filling a prescription for the same treatment after the period covered by the previous prescription. Comparison of persistence by biologic class involved using propensity score-weighted Cox models (inverse probability treatment weighting) and adjustment of specific systemic nonbiologics (time-dependent variables).We included 8693 patients [mean (SD) age 50 (14) years; 50.5% male]; 2824 (32.5%) started TNFi, 1561 (18.0%) IL-12/IL-23i, 2707 (31.1%) IL-17i and 1601 (18.4%) IL-23i. Overall, 1- and 3-year persistence rates were 60% and 30%, respectively. After weighting and adjustment, persistence was longer with IL-12/IL-23i [weighted hazard ratio (HRw) 0.68, 95% confidence interval (CI) 0.62-0.76)], IL-17i (HRw 0.70, 95% CI 0.64-0.78) and IL-23i (HRw 0.36, 95% CI 0.31-0.42) than TNFi, except after first-line IL-17i treatment, with no difference between IL-12/IL-23i, IL-17i and TNFi second-line persistence. Persistence was longer with IL-23i as a second-line treatment than IL-12/IL-23i (HRw 0.53, 95% CI 0.44-0.63) and IL-17i (HRw 0.51, 95% CI 0.44-0.60), regardless of first-line treatment, with no difference seen between IL-12/IL-23i and IL-17i (HRw 0.97, 95% CI 0.87-1.09).This real-life study suggests the longer persistence of IL-23i than TNFi, IL-17i and IL-12/IL-23i as second-line treatment for psoriasis. Persistence rates for all biologics remained low at 3 years.
BMP5 contributes to hepcidin regulation and systemic iron homeostasis in mice
Authors: Xia Xiao, Yang Xu, Gillian A. Moschetta, Yang Yu, Allison L. Fisher, Víctor M. Alfaro-Magallanes, Shasta McMillen, Sydney Phillips, Chia-Yu Wang, Jan Christian, Jodie L. Babitt
Journal: Blood (2023)
Y-Linked Copy Number Polymorphism of Target of Rapamycin Is Associated with Sexual Size Dimorphism in Seed Beetles
Authors: Philipp Kaufmann, R Axel W Wiberg, Konstantinos Papachristos, Douglas G Scofield, Christian Tellgren-Roth, Elina Immonen
Journal: Molecular Biology and Evolution (2023)

Abstract The Y chromosome is theorized to facilitate evolution of sexual dimorphism by accumulating sexually antagonistic loci, but empirical support is scarce. Due to the lack of recombination, Y chromosomes are prone to degenerative processes, which poses a constraint on their adaptive potential. Yet, in the seed beetle, Callosobruchus maculatus segregating Y linked variation affects male body size and thereby sexual size dimorphism (SSD). Here, we assemble C. maculatus sex chromosome sequences and identify molecular differences associated with Y-linked SSD variation. The assembled Y chromosome is largely euchromatic and contains over 400 genes, many of which are ampliconic with a mixed autosomal and X chromosome ancestry. Functional annotation suggests that the Y chromosome plays important roles in males beyond primary reproductive functions. Crucially, we find that, besides an autosomal copy of the gene target of rapamycin (TOR), males carry an additional TOR copy on the Y chromosome. TOR is a conserved regulator of growth across taxa, and our results suggest that a Y-linked TOR provides a male specific opportunity to alter body size. A comparison of Y haplotypes associated with male size difference uncovers a copy number variation for TOR, where the haplotype associated with decreased male size, and thereby increased sexual dimorphism, has two additional TOR copies. This suggests that sexual conflict over growth has been mitigated by autosome to Y translocation of TOR followed by gene duplications. Our results reveal that despite of suppressed recombination, the Y chromosome can harbor adaptive potential as a male-limited supergene.
Retraction: Cyclic AMP/PKA-dependent paradoxical activation of Raf/MEK/ERK signaling in polycystin-2 defective mice treated with sorafenib
Journal: Hepatology (2023)

Retraction Manuscript for DOI: 10.1002/hep.25872 https://journals.lww.com/hep/Fulltext/2012/12000/Cyclic_AMP_PKA_dependent_paradoxical_activation_of.68.aspx
Zanubrutinib Versus Ibrutinib in Symptomatic Waldenström Macroglobulinemia: Final Analysis From the Randomized Phase III ASPEN Study
Authors: Meletios A. Dimopoulos, Stephen Opat, Shirley D'Sa, Wojciech Jurczak, Hui-Peng Lee, Gavin Cull, Roger G. Owen, Paula Marlton, Björn E. Wahlin, Ramon Garcia-Sanz, Helen McCarthy, Stephen Mulligan, Alessandra Tedeschi, Jorge J. Castillo, Jaroslaw Czyz, Carlos Fernández de Larrea, David Belada, Edward Libby, Jeffrey Matous, Marina Motta, Tanya Siddiqi, Monica Tani, Marek Trněný, Monique C. Minnema, Christian Buske, Veronique Leblond, Steven P. Treon, Judith Trotman, Wai Y. Chan, Jingjing Schneider, Heather Allewelt, Sheel Patel, Aileen Cohen, Constantine S. Tam
Journal: Journal of Clinical Oncology (2023)

The phase III ASPEN study demonstrated the comparable efficacy and improved safety of zanubrutinib versus ibrutinib in patients with Waldenström macroglobulinemia (WM). Here, we report long-term follow-up outcomes from ASPEN. The primary end point was the sum of very good partial response (VGPR) + complete response (CR) rates; secondary and exploratory end points were also reported. Cohort 1 comprised 201 patients (myeloid differentiation primary response 88-mutant WM: 102 receiving zanubrutinib; 99 receiving ibrutinib); cohort 2 comprised 28 patients (myeloid differentiation primary response 88 wild-type WM: 28 zanubrutinib; 26 efficacy evaluable). At 44.4-month median follow-up, VGPR + CR rates were 36.3% with zanubrutinib versus 25.3% with ibrutinib in cohort 1 and 30.8% with one CR in cohort 2. In patients with CXC motif chemokine receptor 4 mutation, VGPR + CR rates were 21.2% with zanubrutinib versus 10.0% with ibrutinib (cohort 1). Median progression-free survival and overall survival were not reached. Any-grade adverse events (AEs) of diarrhea (34.7%
Cathepsin D overexpression in the nervous system rescues lethality and Aβ42 accumulation of cathepsin D systemic knockout in vivo
Authors: Xiaosen Ouyang, Willayat Y. Wani, Gloria A. Benavides, Matthew J. Redmann, Hai Vo, Thomas van Groen, Victor M. Darley-Usmar, Jianhua Zhang
Journal: Acta Pharmaceutica Sinica B (2023)

The lysosome is responsible for protein and organelle degradation and homeostasis and the cathepsins play a key role in maintaining protein quality control. Cathepsin D (CTSD), is one such lysosomal protease, which when deficient in humans lead to neurolipofuscinosis (NCL) and is important in removing toxic protein aggregates. Prior studies demonstrated that CTSD germ-line knockout-
Cotransfer of antigen and contextual information harmonizes peripheral and lymph node conventional dendritic cell activation
Authors: Chiara Pirillo, Sarwah Al Khalidi, Anna Sims, Ryan Devlin, Huailong Zhao, Rute Pinto, Seema Jasim, Patrick A. Shearer, Amy L. Shergold, Hannah Donnelly, Alberto Bravo-Blas, Colin Loney, Georgia Perona-Wright, Ed Hutchinson, Ed W. Roberts
Journal: Science Immunology (2023)

T cell responses against infections and cancer are directed by conventional dendritic cells (cDCs) in lymph nodes distant from the site of challenge. Migratory cDCs, which travel from the tissue to the lymph node, not only drive initial T cell activation but also transfer antigen to lymph node–resident cDCs. These resident cells have essential roles defining the character of the resulting T cell response; however, it is unknown how they can appropriately process and present antigens to suitably direct responses given their spatial separation. Here, using a novel strain of influenza A and a modified melanoma model, we show that tissue and lymph node cDC activation is harmonized and that this is driven by cotransfer of contextual cues. In the tumor, incomplete cDC activation in the tumor microenvironment is mirrored by lymph node–resident cDCs, whereas during influenza infection, pathogen-associated molecular patterns cotransferred with antigen drive TLR signaling in resident cDCs and their subsequent robust activation. This cotransfer mechanism explains how individual antigens can be handled distinctly by resident cDCs and how signals driving poor tumoral cDC activation further impact the lymph node. Our findings clarify how tissue context dictates antigenic and, consequently, T cell fate in the lymph node.
Cancer stem cells as the source of tumor associated myoepithelial cells in the tumor microenvironment developing ductal carcinoma in situ
Authors: Said M. Afify, Ghmkin Hassan, Maram H. Zahra, Hend M. Nawara, Hagar A. Abu Quora, Amira Osman, Hager Mansour, Kazuki Kumon, Akimasa Seno, Ling Chen, Ayano Satoh, David S. Salomon, Masaharu Seno
Journal: Biomaterials (2023)
The F-box-only protein 44 regulates pregnane X receptor protein level by ubiquitination and degradation
Authors: Rebecca R. Florke Gee, Andrew D. Huber, Jing Wu, Richa Bajpai, Allister J. Loughran, Shondra M. Pruett-Miller, Taosheng Chen
Journal: Acta Pharmaceutica Sinica B (2023)

Pregnane X receptor (PXR) is a ligand-activated nuclear receptor that transcriptionally upregulates drug-metabolizing enzymes [
A high-throughput Gaussia luciferase reporter assay for screening potential gasdermin E activators against pancreatic cancer
Authors: Yang Liu, Xiaowei Zhang, Ping Zhang, Tingting He, Weitao Zhang, Dingyuan Ma, Ping Li, Jun Chen
Journal: Acta Pharmaceutica Sinica B (2023)

It is discovered that activated caspase-3 tends to induce apoptosis in gasdermin E (GSDME)-deficient cells, but pyroptosis in GSDME-sufficient cells. The high GSDME expression and apoptosis resistance of pancreatic ductal adenocarcinoma (PDAC) cells shed light on another attractive strategy for PDAC treatment by promoting pyroptosis. Here we report a hGLuc-hGSDME-PCA system for high-throughput screening of potential GSDME activators against PDAC. This screening system neatly quantifies the oligomerization of GSDME-N to characterize whether pyroptosis occurs under the stimulation of chemotherapy drugs. Based on this system, ponatinib and perifosine are screened out from the FDA-approved anti-cancer drug library containing 106 compounds. Concretely, they exhibit the most potent luminescent activity and cause drastic pyroptosis in PDAC cells. Further, we demonstrate that perifosine suppresses pancreatic cancer by promoting pyroptosis via caspase-3/GSDME pathway both in vitro and in vivo. Collectively, this study reveals the great significance of hGLuc-hGSDME-PCA in identifying compounds triggering GSDME-dependent pyroptosis and developing promising therapeutic agents for PDAC.
2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease
Authors: Salim S. Virani, L. Kristin Newby, Suzanne V. Arnold, Vera Bittner, LaPrincess C. Brewer, Susan Halli Demeter, Dave L. Dixon, William F. Fearon, Beverly Hess, Heather M. Johnson, Dhruv S. Kazi, Dhaval Kolte, Dharam J. Kumbhani, Jim LoFaso, Dhruv Mahtta, Daniel B. Mark, Margo Minissian, Ann Marie Navar, Amit R. Patel, Mariann R. Piano, Fatima Rodriguez, Amy W. Talbot, Viviany R. Taqueti, Randal J. Thomas, Sean van Diepen, Barbara Wiggins, Marlene S. Williams
Journal: Journal of the American College of Cardiology (2023)
Future medicine: from molecular pathways to the collective intelligence of the body
Authors: Eric Lagasse, Michael Levin
Journal: Trends in Molecular Medicine (2023)

The remarkable anatomical homeostasis exhibited by complex living organisms suggests that they are inherently reprogrammable information-processing systems that offer numerous interfaces to their physiological and anatomical problem-solving capacities. We briefly review data suggesting that the multiscale competency of living forms affords a new path for biomedicine that exploits the innate collective intelligence of tissues and organs. The concept of tissue-level allostatic goal-directedness is already bearing fruit in clinical practice. We sketch a roadmap towards 'somatic psychiatry' by using advances in bioelectricity and behavioral neuroscience to design methods that induce self-repair of structure and function. Relaxing the assumption that cellular control mechanisms are static, exploiting powerful concepts from cybernetics, behavioral science, and developmental biology may spark definitive solutions to current biomedical challenges.
Experiences of HIV among global Indigenous populations through the lens of the UN Declaration on the Rights of Indigenous Peoples
Authors: Eryn Braley, Jorden Hendry, McKenzie Braley, Chenoa Cassidy-Matthews, Shannon Waters, Wenecwtsin Christian, Patricia Spittal, Lou Demerais, Sherri Pooyak, Danièle Behn Smith, Kate Jongbloed
Journal: The Lancet HIV (2023)
Longitudinal studies of challenging behaviours in autistic children and adults: A systematic review and meta-analysis
Authors: Dawn Adams, Nicole Dargue, Jessica Paynter
Journal: Clinical Psychology Review (2023)

Autistic children and adults are at increased risk of showing behaviours that may be described as challenging, however, little is known about whether or how these behaviours may change over time. Given the profound impact that challenging behaviour can have on both the autistic individual and their support network, it is critical that the trajectory of challenging behaviours be better understood. This systematic review and meta-analysis identified and synthesised observational longitudinal studies of challenging behaviour in autistic individuals. Fifty-six studies were included in the systematic review, and the effect sizes of 37 independent samples arising from 34 of these reports were examined through meta-analysis. Crucially, across the 37 samples, scores on the measures of challenging behaviour reduced by a small, yet significant, extent over time. Although age of the sample at baseline assessment did not moderate the effect, the time between the baseline assessment and final follow-up and age at final follow-up both moderated the magnitude of the effect, with challenging behaviour scores reducing to a larger extent in (a) studies with longer intervals between baseline and final follow-up and (b) studies with older samples at follow-up. The results from the current systematic review and meta-analysis have both theoretical and practical implications for understanding challenging behaviour over time in autistic individuals. Avenues for future research are also highlighted that may allow better understanding, and therefore support of, challenging behaviour in autistic individuals.
Obesity-induced dysregulation of skin-resident PPARγ+ Treg cells promotes IL-17A-mediated psoriatic inflammation
Authors: Pulavendran Sivasami, Cody Elkins, Pamela P. Diaz-Saldana, Kyndal Goss, Amy Peng, Michael Hamersky, Jennifer Bae, Miaoer Xu, Brian P. Pollack, Edwin M. Horwitz, Christopher D. Scharer, Lindsey Seldin, Chaoran Li
Journal: Immunity (2023)
The gut protist Tritrichomonas arnold restrains virus-mediated loss of oral tolerance by modulating dietary antigen-presenting dendritic cells
Authors: Luzmariel Medina Sanchez, Magdalena Siller, Yanlin Zeng, Pamela H. Brigleb, Kishan A. Sangani, Ariadna S. Soto, Clarisse Engl, Colin R. Laughlin, Mohit Rana, Lauren Van Der Kraak, Surya P. Pandey, Mackenzie J. Bender, Britney Fitzgerald, Lee Hedden, Kay Fiske, Gwen M. Taylor, Austin P. Wright, Isha D. Mehta, Syed A. Rahman, Heather J. Galipeau, Steven J. Mullett, Stacy L. Gelhaus, Simon C. Watkins, Premysl Bercik, Timothy J. Nice, Bana Jabri, Marlies Meisel, Jishnu Das, Terence S. Dermody, Elena F. Verdú, Reinhard Hinterleitner
Journal: Immunity (2023)
Targeted removal of macrophage-secreted interleukin-1 receptor antagonist protects against lethal Candida albicans sepsis
Authors: Hang Thi Thuy Gander-Bui, Joëlle Schläfli, Johanna Baumgartner, Sabrina Walthert, Vera Genitsch, Geert van Geest, José A. Galván, Carmen Cardozo, Cristina Graham Martinez, Mona Grans, Sabine Muth, Rémy Bruggmann, Hans Christian Probst, Cem Gabay, Stefan Freigang
Journal: Immunity (2023)

Invasive fungal infections are associated with high mortality rates, and the lack of efficient treatment options emphasizes an urgency to identify underlying disease mechanisms. We report that disseminated Candida albicans infection is facilitated by interleukin-1 receptor antagonist (IL-1Ra) secreted from macrophages in two temporally and spatially distinct waves. Splenic CD169+ macrophages release IL-1Ra into the bloodstream, impeding early neutrophil recruitment. IL-1Ra secreted by monocyte-derived tissue macrophages further impairs pathogen containment. Therapeutic IL-1Ra neutralization restored the functional competence of neutrophils, corrected maladapted hyper-inflammation, and eradicated the otherwise lethal infection. Conversely, augmentation of macrophage-secreted IL-1Ra by type I interferon severely aggravated disease mortality. Our study uncovers how a fundamental immunoregulatory mechanism mediates the high disease susceptibility to invasive candidiasis. Furthermore, interferon-stimulated IL-1Ra secretion may exacerbate fungal dissemination in human patients with secondary candidemia. Macrophage-secreted IL-1Ra should be considered as an additional biomarker and potential therapeutic target in severe systemic candidiasis.
Carnobacterium maltaromaticum boosts intestinal vitamin D production to suppress colorectal cancer in female mice
Authors: Qing Li, Hung Chan, Wei-Xin Liu, Chang-An Liu, Yunfei Zhou, Dan Huang, Xueliang Wang, Xiaoxing Li, Chuan Xie, Wing Ying-Zhi Liu, Xian-Song Wang, Siu Kin Ng, Hongyan Gou, Liu-Yang Zhao, Winnie Fong, Lanping Jiang, Yufeng Lin, Guijun Zhao, Feihu Bai, Xiaodong Liu, Huarong Chen, Lin Zhang, Sunny Hei Wong, Matthew Tak Vai Chan, William Ka Kei Wu, Jun Yu
Journal: Cancer Cell (2023)

Carnobacterium maltaromaticum was found to be specifically depleted in female patients with colorectal cancer (CRC). Administration of C. maltaromaticum reduces intestinal tumor formation in two murine CRC models in a female-specific manner. Estrogen increases the attachment and colonization of C. maltaromaticum via increasing the colonic expression of SLC3A2 that binds to DD-CPase of this bacterium. Metabolomic and transcriptomic profiling unveils the increased gut abundance of vitamin D-related metabolites and the mucosal activation of vitamin D receptor (VDR) signaling in C. maltaromaticum-gavaged mice in a gut microbiome- and VDR-dependent manner. In vitro fermentation system confirms the metabolic cross-feeding of C. maltaromaticum with Faecalibacterium prausnitzii to convert C. maltaromaticum-produced 7-dehydrocholesterol into vitamin D for activating the host VDR signaling. Overall, C. maltaromaticum colonizes the gut in an estrogen-dependent manner and acts along with other microbes to augment the intestinal vitamin D production to activate the host VDR for suppressing CRC.
Drug discovery by targeting the protein–protein interactions involved in autophagy
Authors: Honggang Xiang, Mi Zhou, Yan Li, Lu Zhou, Renxiao Wang
Journal: Acta Pharmaceutica Sinica B (2023)

Autophagy is a cellular process in which proteins and organelles are engulfed in autophagosomal vesicles and transported to the lysosome/vacuole for degradation. Protein-protein interactions (PPIs) play a crucial role at many stages of autophagy, which present formidable but attainable targets for autophagy regulation. Moreover, selective regulation of PPIs tends to have a lower risk in causing undesired off-target effects in the context of a complicated biological network. Thus, small-molecule regulators, including peptides and peptidomimetics, targeting the critical PPIs involved in autophagy provide a new opportunity for innovative drug discovery. This article provides general background knowledge of the critical PPIs involved in autophagy and reviews a range of successful attempts on discovering regulators targeting those PPIs. Successful strategies and existing limitations in this field are also discussed.
Re: Gyrithe Lynghøj Pedersen, Marie Schmidt Erikson, Karin Mogensen, Susanne Rosthøj, Gregers Gautier Hermann. Outpatient Photodynamic Diagnosis-guided Laser Destruction of Bladder Tumors Is as Good as Conventional Inpatient Photodynamic Diagnosis-guided Transurethral Tumor Resection in Patients with Recurrent Intermediate-risk Low-grade Ta Bladder Tumors. A Prospective Randomized Noninferiority Clinical Trial. Eur Urol 2023;83:125–30
Authors: Deng-Xiong Li, De-Chao Feng, Shi Deng
Journal: European Urology (2023)